Gaucher Disease: In the largest neuropathological investigation of its kind in Gaucher disease, we studied 14 patients with all three phenotypes of this disease. We found a unique pathologic pattern of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex. While this finding was common to all three phenotypes of Gaucher disease, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b, were involved in all patients with this disorder. Immunohistochemical staining with anti-glucocerebrosidase antibody precisely matched the pathologic localization with dense staining of CA4-2. We identified numerous brain stem-type Lewy bodies in hippocampal CA4-2 neurons in two patients with type 1 GD and parkinsonism. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity in Gaucher disease, neuronal cytotoxicity and cytotoxic Lewy body formation. Fabry Disease: One of the major goals of the Branch is to develop effective treatment for patients with hereditary neurometabolic disorders. Second to Gaucher disease, the most prevalent condition in this category is Fabry disease. Patients with this disorder have a severely painful peripheral neuropathy, premature strokes and myocardial infarctions, and ultimately, complete renal failure. During the reporting year, we performed an open-label continuation study of enzyme replacement therapy (ERT) for Fabry disease. The missing enzyme, alpha-galactosidase A, was prepared in a Good Manufacturing Practices Facility using a continuous human cell line as source of the enzyme. Patients receiving the study drug had significant reduction of the painful acroparesthesias associated with this disorder. Patients who had been initially on placebo experienced the same benefit when treated with enzyme. Additional findings revealed that patients receiving the enzyme had an improvement of their ability to sense cold and warm temperature and correction of their sweating deficiency. Using MRI and arterial spin-tagging method we showed that brain damage in Fabry patients is associated with increased cerebral blood flow. ERT reversed the cerebral hyper-perfusion in patients with Fabry disease. ERT has been approved for patients with Fabry disease in the European Union and 15 other countries. Mucolipidosis IV: We invstigated 28 patients with this autosomal recessive neurogenetic disorder and identified mutations the protein called mucolipin in all of them. All of the patients had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had an iron deficiency anemia. MRI of the head showed consistent characteristic findings of a thin corpus callosum. This condition remained unchanged during the follow-up period extending over several years. Prominent abnormalities of speech, hand-usage, and swallowing were also noted. Correlation of the genotype with the neurological handicap and the degree of dysplasia of the corpus callosum was observed. We concluded that mucolipidosis IV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay the correct diagnosis of this condition. Leukodystrophies: We demonstrated mutations in subunits of the eucaryotic initiation factor 2B (eIF2B) in patients with a leukodystrophy that was first identified by DMNB in 1994 which at the time was called Childhood Ataxia with CNS Hypomyelination (CACH). Patients with CACH develop a progressive neurological deterioration in childhood, adolescence and sometimes in adulthood. The clinical decline is often initiated or worsens after stresses such as a mild head trauma or an intercurrent febrile illness. eIF2B is a protein complex that is essential for the regulation of protein synthesis, particularly in response to stress. We discovered that patients with Cree leukoencephalopathy, a very severe genetic disease of infancy, also have mutations in eIF2B. Brains of patients with Cree leukoencephalopathy were found to have the same "foamy" oligodendrocytes that we previously described as a hallmark of CACH. We also found that patients with another leukodystrophy we described in 1997 and termed ovarioleukodystrophy also have mutations in subunits of the protein eIF2B. This neurogenetic complex comprises one of the most common leukodystrophy syndromes. It is likely that these investigations will lead to a better understanding of myelination and maintenance of the myelin sheath, particularly in relationship to stressful situations and conditions.